Project 1 Project Summary/Abstract Abnormal deposits of tau protein in neurons along with extracellular neuritic plaques containing fibrillar amyloid are the pathologic hallmarks of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) and positron emission tomography (PET) measures of amyloid can detect abnormalities years to decades before clinical symptoms develop, but pathologic tau in the brain and CSF is more closely related to neuronal injury and death (neurodegeneration) than pathologic amyloid. Very recently, a novel 18F-labeled PET tracer targeting pathologic tau, T807, has shown great promise for detecting the amount and locations of abnormal tau deposition in the brains of living persons which was not previously possible. Validation of this new technology is needed to determine how well it works for detecting tau pathology and how it compares with existing CSF measures. In the long term, PET studies with T807 may be used to accelerate the development of therapies for AD by identifying individuals at high risk for near-term or ongoing neuronal injury who may benefit the most from therapy and by measuring response to these therapies during clinical trials based on decreasing brain T807 binding on serial imaging studies. This proposal focuses on the necessary next steps to compare T807-PET measures with existing CSF markers of tau. We will take advantage of well-characterized, biomarker-defined individuals through the Knight ADRC to perform T807-PET studies in groups of participants across the spectrum of AD ranging from normal controls to early AD dementia. The amount of brain T807 binding will be compared to amounts of CSF tau biomarkers measured in each individual, and the ability of these PET and CSF measures to predict cognitive status at baseline and 2-4 years later will be compared. In a subset of these participants, we will repeat T807- PET imaging (and CSF collection) to assess how rapidly T807 binding changes over time in asymptomatic individuals with and without abnormal CSF amyloid. We hypothesize that higher brain T807 binding will occur in those with more advanced AD pathology and will predict greater cognitive impairment and decline than those with lower brain T807 binding. This study will be conducted through the following Specific Aims: Aim 1: Examine the association among T807-PET measures of PHF-tau, concentrations of CSF biomarkers, and cognitive performance. Aim 2. Characterize the amount and spatial distribution of T807-PET measures in healthy aging, preclinical AD, and early symptomatic AD. Aim 3 (Discovery): Evaluate the change in T807-PET measures over time in asymptomatic amyloid-positive individuals and its association with changes in concentrations of CSF biomarkers.